Key hepatoprotective roles of mitochondria in liver regeneration

Abstract

Treatment of advanced liver disease using surgical modalities is possible due to the liver's innate ability to regenerate following resection. Several key cellular events in the regenerative process converge at the mitochondria, implicating their crucial roles in liver regeneration. Mitochondria enable the regenerating liver to meet massive metabolic demands by coordinating energy production to drive cellular proliferative processes and vital homeostatic functions. Mitochondria are also involved in terminating the regenerative process by mediating apoptosis. Studies have shown that attenuation of mitochondrial activity results in delayed liver regeneration, and liver failure following resection is associated with mitochondrial dysfunction. Emerging mitochondria therapy (i.e., mitotherapy) strategies involve isolating healthy donor mitochondria for transplantation into diseased organs to promote regeneration. This review highlights mitochondria's inherent role in liver regeneration.

Keywords: liver regeneration; mitochondria; mitochondrial bioenergetics; mitochondrial therapy; partial hepatectomy.

Graphical abstract

Figure 1.

Mitochondria present two predominating morphologies throughout the cell cycle: a hyperfused reticulum and multiple fragmented mitochondria. This occurs in coordination with activation of phase-specific CDKs that are required for advancement through the cell cycle. Cyclin D1 first associates with CDK4 and promotes progression through G1 phase. During late G1 phase, fusion of the mitochondrial network is initiated by Mfn 1, Mfn 2, and Opa1. The reticulum is associated with enhanced oxidative capacity which induces accumulation of Cyclin E. Association of Cyclin E1 with CDK2 is essential to advance through the G1/S-phase check point. The reticulum begins to fragment via fission at the onset of S phase, which is mediated by Drp1, Fis1, Mff, MiD51, and MiD49. Cyclin A2 is also synthesized during S phase, which interacts with CDK2 to initiate DNA replication. After the S phase, the cell enters G2 phase to prepare for mitosis (i.e., M phase). Fission continues through M phase to promote equal distribution of mitochondria between the resulting daughter cells. The phosphorylative effects of Cyclin B1/CDK1 result in the dissolution of the nuclear envelope initiating mitosis. CDK, cyclin-dependent kinase; Fis1, fission 1; Mff, mitochondrial fission factor; Mfn1, mitofusin 1; Mfn2, mitofusin 2; Opa1, optic atrophy 1.